It has been suggested that the ability to drive a car is impaired in patients with cirrhosis of the liver and minimal hepatic encephalopathy (MHE). However, the only study using an on-road driving test did not reveal such an impairment. In a prospective controlled study, we evaluated patients with cirrhosis of the liver for MHE and the ability to drive a car. MHE was diagnosed using three psychometric tests: Number Connection Test Part A, Digit Symbol Test, and a Complex Choice Reaction Test. In a standardized on-road driving test (22 miles, 90 minutes), designed for patients with brain impairment, a professional driving instructor blind to the subjects' diagnosis and test results assessed the driving performance. Four global driving categories (car handling, adaptation to traffic situation, cautiousness, maneuvering), 17 specific driving actions (e.g., changing lanes, overtaking, etc.), and a total score of driving performance were rated using a 6-point scale. Of 274 consecutive patients with liver cirrhosis, 48 fulfilled the medical and driving inclusion criteria, 14 of them with and 34 without MHE. Forty-nine subjects in a stable phase of chronic gastroenterological diseases and with normal liver findings served as controls. The total driving score of patients with MHE was significantly reduced in comparison to either cirrhotic patients without MHE or to controls (P <.05). Significant differences in ratings were found in the following driving categories: car handling, adaptation, and cautiousness. Significant differences were also found in specific driving actions. The instructor had to intervene in the driving of 5 of the 14 MHE patients to avoid an accident, significantly more than in cirrhotic patients without MHE and in controls. There was no significant difference in any driving category or specific driving action in cirrhotic patients without MHE compared to controls. In conclusion, fitness to drive a car can be impaired in patients with MHE. Therefore, patients with liver cirrhosis should be tested for MHE and informed in the case of abnormal test results. Therapy known to improve psychometric test results should be initiated.

A prospective randomized study on sixty patients was conducted to investigate the effects of a fish oil containing total parenteral nutrition (TPN) regimen in the postoperative period on lymphocyte subset distribution, proliferation, cytokine production and interleukin-2 receptor (IL-2R) expression. Patients who underwent large bowel surgery were divided into three groups. Nineteen patients received TPN with fish oil (0.2 g/kg body weight per day) plus soybean oil (1.0 g/kg per day), twenty patients received soybean oil (1.2 g/kg per day), and twenty-one patients who were on a fat-free regimen served as the control group. Natural killer (NK) cells, total, B-, T-, T-4-, T-8-lymphocytes, proliferation of lymphocytes, in vitro production of IL-2, IFN-gamma, TNF-alpha, and IL-2R expression were measured. Fish oil administration did not affect subset distribution and proliferation of lymphocytes. Production of interleukin-2 (IL-2), interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) was augmented, and IL-2R expression less enhanced compared with the controls. It is concluded that administration of 0.2 g/kg per day fish oil after a moderate surgical stress is not immunosuppressive, but enhances the production of IFN-gamma, TNF-alpha and possibly IL-2.

Enrichment in hippurate has been measured to indicate precursor enrichment during glycine tracer infusion studies to estimate fractional synthetic rates of individual hepatic export proteins. However, hippurate tends to overestimate precursor enrichment. Since glycine is rapidly converted to serine by liver cells, we compared tracer enrichment in hippurate and serine with that of glycine incorporated into apolipoprotein (apo) B-100. Ten healthy control subjects were studied in the postabsorptive state during an 8-hour primed-constant infusion of [15N]glycine (10 μmol · kg−1 · h−1). Apo B of very-low-density lipoprotein (VLDL) was isolated by standard ultracentrifugation and isopropanol precipitation. Glycine and serine were isolated from plasma and hydrolyzed apo B, hippurate was isolated from plasma, and [15N]enrichment was determined by gas chromatography-mass spectrometry. Enrichment in serine and glycine isolated from apo B was identical at all time points, and their enrichment in apo B increased asymptotically, approaching an apparent plateau (mean ± SD: 91% ± 10% of calculated plateau at 8 hours) that was taken to represent hepatic protein precursor enrichment. Enrichment in both plasma serine and hippurate followed a biphasic pattern and continued to increase until the end of the study, raising the possibility that precursor enrichment had not reached a steady state during the study. The apo B plateau was lower (factor 0.76 ± 0.27) than the final enrichment in hippurate and higher (factor 1.38 ± 0.36) than that in plasma serine; however, predictions of protein precursor enrichment based on either metabolite were flawed by a large coefficient of variation (35% v 26%). We conclude that glycine enrichment in the hepatic protein precursor pool may not be constant during an 8-hour infusion study, and that only a rough approximation of this level may be obtained using either enrichment in plasma hippurate or plasma serine.

Effects of palmitic, stearic, oleic, and linoleic acid on mitogen‐induced DNA synthesis, on production of IL‐1β, IL‐2, IFN‐gamma, and TNF‐α, and on IL‐2R expression were determined in human peripheral lymphocytes. Free fatty acids (FFA) were added over a wide range of concentrations to cells cultured under serum free conditions with fatty acid free albumin. DNA synthesis was stimulated by low and inhibited by high FFA concentrations. Physiologica concentrations were stimulatory, except for linoleic acid. Cytokine production became affected by all FFA tested. Palmitic acid enhanced the release of IFN‐gamma at concentrations that diminished TNF‐α production. Saturated fatty acids were significantly more potent than unsaturated fatty acids in affecting cytokine production. IFN‐gamma secretion was significantly more stimulated or inhibited by the various FFA compared with the other cytokines. IL‐2R expression correlated with the production of IL‐2. When tested in combination, stimulatory as well as inhibitory effects of the individual FFA became attenuated. It is suggested that palmitic, stearic, oleic, and linoleic acid are physiological regulators of DNA synthesis and cytokine release in human peripheral lymphocytes. Modulation of FFA ratios may be an effective means for the fine tuning of the immune system. As secretory mechanisms of cytokines appear to exhibit substrate specificity for FFA, the release of individual cytokines may be selectively influenced by FFA. © 1994 Wiley‐Liss, Inc.

Amino-acid degradation, interleukin-2 (IL-2) production, and DNA synthesis were analysed in concanavalin A (ConA)-treated peripheral venous lymphocytes from healthy blood donors and in lymphocytes from patients after unevenful abdominal surgery. ConA augmented (CO2)-C-14 production from (U-C-14) glutamine (492 +/- 44 vs. 2274 +/- 174 pmol/10(6) cells x 40 min-1) while it had little effect on (CO2)-C-14 production from (1-C-14) leucine (132 +/- 8 vs. 161 +/- 17 pmol/10(6) cells x 40 min-1) compared with the respective controls. Similar effects on amino-acid degradation were observed in response to surgery. Glutamine but not leucine amplified IL-2 production from ConA-treated cells, and it was a prerequisite for DNA synthesis. In lymphocytes from operated patients, spontaneous incorporation of (H-3) thymidine was higher on day 3 and day 6 (310 and 2660 cpm/10(6) cells) after surgery, compared with the pre-operative day (68 cpm/10(6) cells; median values). These results indicate 1) that glutamine is more critical than leucine for the immune function of T-lymphocytes, and 2) that lymphocytes from patients undergoing uneventful abdomional surgery have become stimulated in vivo. It is suggested that these cells may qualify as a suitable experimental model to study the metabolic basis for immunologic functions after antigenic stimulation in vivo.

Characteristics of glutamine transport, its substrate specificity, and its pattern of competitive and non-competitive inhibition in response to amino acid analogues were determined in peripheral human lymphocytes, incubated with or without concanavalin A (Con A). Maximum capacity of transport (Vmax) at 37 degrees C and 136.9 mM Na+ was 30 pmol/10(6) cells/30 seconds, while the apparent Km was 142 microM. In cells exposed to 10 mM histidine, asparagine, serine, or leucine transport of glutamine declined to 28%, 15%, 17%, and 21%, respectively, of the rates in controls. Inhibition by histidine (Ki = 0.58 mM) and serine (Ki = 0.25 mM) was competitive, by leucine was non-competitive (Ki = 0.64), while alpha-methylamino-isobutyric acid and 2-amino carboxy-bicyclo (2.2.1)-heptane had no effect. In cells cultured for 24 hours with or without 10 micrograms/ml Con A, the apparent Km was 70 microM vs. 89 microM and Vmax 73 vs. 26 pmol/10(6) cells/30 seconds. Sodium depletion (9.0 mM NaCl) greatly diminished glutamine transport in resting and stimulated cells. Inhibition of glutamine transport by serine was sodium sensitive, while inhibition by histidine and asparagine was not. Serine had no competitive effect in sodium-depleted media. The data demonstrate what appear to be two carrier systems for glutamine, sodium sensitive and sodium insensitive. It is suggested that glutamine transport into lymphocytes occurs via processes similar to System N and System ASC described in other cells, with System ASC as the sodium-sensitive component. Con A augments the capacity rather than the affinity of glutamine transporting systems.

Transport and pathways of leucine and glutamine degradation were evaluated in resting human peripheral lymphocytes and compared with the changes induced by concanavalin A (ConA). Cells were incubated with [1‐14C]leucine (0.15 mM), [U‐14C]leucine (0.15 mM), or [U‐14C]glutamine (0.4 mM) after culture with or without 2, 5, 7, or 10 μg/ml ConA for 2, 18, or 24 hours, respectively. Initial rates of transport of leucine and glutamine were augmented 2.7‐fold and threefold by the mitogen. Leucine transamination, irreversible oxidation, and catabolism beyond isovaleryl‐CoA were increased by 90%, 20%, and 60%, respectively. Glu‐tamine utilization increased threefold; accumulation of glutamate, aspartate, and ammonia increased by 700%, 50%, and 100%, respectively, and 14CO2 production by about 400% in response to ConA. The results indicate that ConA stimulates to about the same extent transport of leucine and glutamine into lymphocytes. Glutamine is mainly channeled into catabolic pathways, while leucine remains largely preserved. It is suggested that these metabolic changes provide more leucine for incorporation into protein and more N‐ and C‐atoms required for the synthesis of macromolecules and energy from glutamine.

The data indicate that glutamine plays a critical role in the metabolism of human lymphocytes stimulated in vitro and in vivo. The understanding of these processes is a prerequisite if one is to substitute glutamine under conditions of compromised lymphocyte function.

In vivo synthesis of apolipoprotein B 100 (ApoB) was recently determined in man using stable isotopes. With this procedure we analyzed (1) the effect of fasting on synthesis of ApoB from very low density lipoprotein (VLDL) and (2) tracer enrichment in low density lipoprotein (LDL). After a 36-hour fasting period and in the post-absorptive state 4 healthy subjects were given a priming dose (8.7 mumol/kg) of 15N glycine followed by a constant infusion (10 mumol/kg/h for 8 h) to achieve 5% tracer enrichment in the plasma pool of glycine. The K-values, i.e. fractional synthetic rates/hr of ApoB from VLDL were 0.53 +/- 0.26 vs. 0.43 +/- 0.16 (p greater than 0.05). Tracer enrichment in ApoB from LDL at the end of the infusions was 0.19% vs. 1.46% in ApoB from VLDL. The results indicate that (1) in young healthy postabsorptive individuals about 40% of ApoB from VLDL in plasma is synthesized per hour, (2) fasting does not materially affect fractional ApoB synthesis and (3) at 5% 15N enrichment in plasma glycine, tracer enrichment in ApoB from LDL is at the lower limit of detection for the procedure employed.

In this study we investigated the influence of physiological levels of glutamine, isoleucine, and valine on leucine oxidation and transport by peripheral lymphocytes in an in vitro system. The presence of glutamine in the incubation mixture inhibited leucine oxidation by 61%. This effect was not significantly augmented by addition of isoleucine and valine. Leucine transport revealed a Km of 124 mumol/L and a Vmax of 24 pmol/10(6) cells/30 sec. Glutamine inhibited leucine transport by 63%. The capacity of lymphocytes for leucine transport exceeded the capacity for leucine oxidation by a factor of 7.8 (13.6 +/- 0.6 v 1.74 +/- 0.1 pmol/10(6) cells/30 sec). It is concluded that glutamine is a regulator of leucine transport and oxidation in human peripheral lymphocytes, and the inhibition of leucine oxidation by glutamine is not due to an alteration of leucine transport but reflects an intracellular event.

In vivo synthesis of apolipoprotein B 100 (ApoB) was recently determined in man using stable isotopes. With this procedure we analyzed (1) the effect of fasting on synthesis of ApoB from very low density lipoprotein (VLDL) and (2) tracer enrichment in low density lipoprotein (LDL).